The present invention relates to an inhibitor of Helicobacter pylori adhesion and pharmaceutical compositions for oral administration useful for the effective prevention or treatment of peptic ulcers caused by Helicobacter pylori. 
At present it is believed that eradication of H. pylori from the stomach is essential for completely treating peptic ulcers. The combination of an antibiotic and an inhibitor of gastric acid secretion has been generally proposed as a therapy for eradication of H. pylori as described below.
H. pylori is a gram-negative spiral rod-shaped bacterium having flagella at one end and colonizing the human gastric mucosa. B. J. Marshall and J. R. Warren in Australia reported in 1983 that this bacterium was frequently detected in stomach biopsy specimens from patients with gastritis or gastric ulcers.
Since then, many reports have been published based on epidemiological studies, indicating that this bacterium causes gastritis, gastric ulcers, and duodenal ulcers and is associated with diseases such as gastric cancer. Once H. pylori colonizes gastric mucosa, it survives and persists in the stomach and cannot be eradicated, although the immune response to infection by H. pylori is strong, i.e., the antibody titer is high. Therefore, unless H. pylori is completely eliminated from the stomach by antibiotic therapy, the infection will return to the same level as before treatment within about a month after the administration of antibiotics is stopped. Additionally, the pH of the stomach is maintained very low by HCl, which is a strong acid, and therefore most antibiotics tend to be inactivated. For this reason, the combination of an antibiotic and a proton pump inhibitor which strongly suppresses the secretion of gastric acid is utilized for eradication of H. pylori. However, the administration of antibiotics for a long time has the serious problems of increasing antibiotic-resistant strains as well as causing side effects.
An immunological therapy approach using an oral vaccine has been proposed in order to solve problems such as side effects and the increase of antibiotic-resistant strains caused by treatment with antibiotics for the eradication of the bacteria. However, this approach has not been put to practical use. Also, an oral vaccine has problems with respect to the safety of adjutants in its practical application to humans. Additionally, the vaccine is predominantly used for prevention, and therefore it has no effect on patients who have already been infected with H. pylori. 
As an alternative immunotherapy, the use of egg antibodies against H. pylori whole cell has been proposed by Aiba et al. (The Meeting of the 30th Japan Germ-free Animal Gnotobiology Society, Program and Abstracts, p22, Requested Title 18, New Attempt for Inhibiting Helicobacter pylori, January 1997), and in Japanese Patent Application Kokai No. 4-275232 and transactions of Japan Agricultural Chemistry Society, 71, p52, 20p22 (1997). However, the antibodies against H. pylori whole cells cannot completely eliminate H. pylori from the stomach, and therefore do not provide a pharmaceutical composition effective for the prevention or treatment of peptic ulcers.
It is an object of the present invention to provide a pharmaceutical composition for use in preventing or treating diseases caused by H. pylori such as peptic ulcers, the composition being effective and safe without the disadvantages of side effects and an increase in drug-resistant strains which are associated with the use of antibiotics.
Other objects and advantages as well as the nature of the present invention will be apparent from the following description.
Previously the present inventors obtained information with respect to H. pylori adhesion in the gastric mucosa, which is the key to growth thereof in the stomach, which has strong acidity, and we provided specific antibodies against H. pylori urease from eggs for use in completely inhibiting colonization of H. pylori in the gastric mucosa (Japanese Patent Application Kokai No. 10-287585). Namely, the inventors found that H. pylori urease participates in the colonization of H. pylori in gastric mucosa, and in particular that H. pylori urease is an adhesin, and demonstrated that antibodies against H. pylori urease from chicken eggs are effective for inhibiting the H. pylori adhesion in the gastric mucosa by binding to urease as an adhesin of H. pylori. 
The present invention is an improvement on the above-mentioned invention, and it was made based on the discovery that the combination of the above-mentioned antibodies against H. pylori urease and an inhibitor of gastric acid secretion has a synergistic effect which enables a decreased dosage of the antibodies used for complete elimination of H. pylori from the stomach.
In one aspect, the present invention provides an inhibitor composition of H. pylori adhesion in the gastrointestinal tract of a mammal including humans, comprising (1) IgY antibodies obtained from at least one chicken egg laid by a hen which has been immunized with an antigenically effective amount of an isolated Helicobacter pylori urease, wherein said IgY antibodies are capable of specifically binding to Helicobacter pylori urease in the gastrointestinal tract of the mammal, and (2) an inhibitor of gastric acid secretion.
In another aspect, the present invention provides a pharmaceutical composition for preventing and/or treating a disease caused by or associated with Helicobacter pylori in a mammal including humans, comprising a pharmaceutically effective amount of the inhibitor composition comprising (1) IgY antibodies obtained from at least one chicken egg laid by a hen which has been immunized with an antigenically effective amount of an isolated Helicobacter pylori urease, wherein said IgY antibodies are capable of specifically binding to Helicobacter pylori urease in the gastrointestinal tract of the mammal, and (2) an inhibitor of gastric acid secretion, and a pharmaceutically acceptable carrier or diluent.